Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia

Nat Commun. 2021 Dec 14;12(1):7268. doi: 10.1038/s41467-021-27197-5.


Interleukin-7 receptor α (encoded by IL7R) is essential for lymphoid development. Whether acute lymphoblastic leukemia (ALL)-related IL7R gain-of-function mutations can trigger leukemogenesis remains unclear. Here, we demonstrate that lymphoid-restricted mutant IL7R, expressed at physiological levels in conditional knock-in mice, establishes a pre-leukemic stage in which B-cell precursors display self-renewal ability, initiating leukemia resembling PAX5 P80R or Ph-like human B-ALL. Full transformation associates with transcriptional upregulation of oncogenes such as Myc or Bcl2, downregulation of tumor suppressors such as Ikzf1 or Arid2, and major IL-7R signaling upregulation (involving JAK/STAT5 and PI3K/mTOR), required for leukemia cell viability. Accordingly, maximal signaling drives full penetrance and early leukemia onset in homozygous IL7R mutant animals. Notably, we identify 2 transcriptional subgroups in mouse and human Ph-like ALL, and show that dactolisib and sphingosine-kinase inhibitors are potential treatment avenues for IL-7R-related cases. Our model, a resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, demonstrates that IL7R can initiate this malignancy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Survival / genetics
  • Gain of Function Mutation
  • Heterozygote
  • Homozygote
  • Humans
  • Interleukin-7 Receptor alpha Subunit / genetics*
  • Interleukin-7 Receptor alpha Subunit / metabolism
  • Mice
  • Penetrance
  • Precancerous Conditions / genetics
  • Precancerous Conditions / pathology
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Precursor Cells, B-Lymphoid / pathology
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Signal Transduction / drug effects


  • Antineoplastic Agents
  • Interleukin-7 Receptor alpha Subunit
  • Proto-Oncogene Proteins p21(ras)